PROJECT SUMMARY/ABSTRACT Acquired autoimmune thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder characterized by acute episodes of systemic microvascular thrombosis caused by deficiency of ADAMTS13, a von Willebrand factor cleaving protease. TTP is more common in women and African Americans. Plasma exchange has improved survival of acute TTP from <10% to 80-90%; however, long-term adverse health outcomes in adults following recovery from TTP are under recognized. Recent data indicate that TTP survivors have higher mortality than age and sex matched controls and over 60% of TTP survivors demonstrate neurocognitive impairment. In a cohort of 157 TTP survivors at Johns Hopkins Hospital, we found a high rate of incident stroke unrelated to an acute TTP relapse during long-term follow up.Intriguingly, over 50% of TTP survivors did not recover ADAMTS13 activity in remission and low ADAMTS13 activity in remission was associated with a higher risk of stroke. Silent cerebral infarcts are ischemic lesions seen on MRI in patients without neurologic symptoms, which are associated with future stroke and cognitive impairment in the general population. Currently, there are no published studies evaluating the prevalence of silent infarcts in TTP survivors, and their association with future stroke and cognitive impairment. The association of ADAMTS13 in remission with ischemic cerebral events (silent infarct and stroke) is also unknown. Dr. Chaturvedi has established a large prospective cohort of patients with TTP, generated compelling preliminary data regarding the risk of stroke in TTP survivors, and established collaborations throughout Johns Hopkins Hospital to answer these questions. We will use the existing Johns Hopkins Thrombotic Microangiopathy Registry to test the hypothesis that silent cerebral infarcts more common in TTP survivors than an age and sex-matched control population, and are a risk factor for stroke and cognitive impairment (Aim 1). We will evaluate whether low ADAMTS13 activity during TTP remission is associated with cerebral ischemic events (silent infarcts and stroke) (Aim 2). Finally, we will evaluate the association of traditional cardiovascular risk factors and germline variants in ADAMTS13 and complement genes with silent infarcts and stroke (Aim 3). Understanding the epidemiology and risk factors for cerebrovascular and cognitive sequelae of TTP will lead to a pilot study of an intervention (low dose anticoagulation or antiplatelet therapy) to reduce the incidence of silent cerebral infarcts and stroke in high-risk TTP patients and has implications for understanding the role of ADAMTS13 in cerebrovascular disease in other populations. Dr. Chaturvedi's mentors, Dr. Robert Brodsky and Dr. Michael DeBaun, have extensive expertise in thrombotic microangiopathies, rare disease research, and evaluation of cerebrovascular disease. Her additional training proposed will enable her to transition to an independent NIH-funded investigator training and experience in cohort studies in rare disease, genetic epidemiology, and cerebrovascular disease research in hematology.